chr19-18747077-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_015321.3(CRTC1):c.406A>G(p.Met136Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M136R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.24

Publications

1 publications found

Variant links:

Genes affected

CRTC1 (HGNC:16062): (CREB regulated transcription coactivator 1) Enables cAMP response element binding protein binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol; nuclear body; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CRTC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045264363).

BP6

Variant 19-18747077-A-G is Benign according to our data. Variant chr19-18747077-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3836529.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3 link	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 14	ENST00000321949.13	NP_056136.2	Q6UUV9-1
CRTC1	NM_001098482.2 link	c.454A>G	p.Met152Val	missense_variant	Exon 5 of 15		NP_001091952.1	Q6UUV9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC1	ENST00000321949.13 link	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 14	1	NM_015321.3	ENSP00000323332.7	Q6UUV9-1
CRTC1	ENST00000338797.10 link	c.454A>G	p.Met152Val	missense_variant	Exon 5 of 15	1		ENSP00000345001.5	Q6UUV9-2
CRTC1	ENST00000594658.5 link	c.283A>G	p.Met95Val	missense_variant	Exon 4 of 14	1		ENSP00000468893.1	M0QX46
CRTC1	ENST00000601916.1 link	c.181A>G	p.Met61Val	missense_variant	Exon 3 of 10	5		ENSP00000469285.1	M0QXN6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250500

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460724

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111420

Other (OTH)

AF:

0.00

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 06, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.48

T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.045

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.6

N;.;.;.

PhyloP100

6.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

1.3

N;N;.;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.25

MutPred

0.17

Gain of sheet (P = 0.0344);.;.;.;

MVP

0.043

MPC

0.58

ClinPred

0.047

GERP RS

4.8

Varity_R

0.086

gMVP

0.11

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over